Test Id : HIESG

For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Targeted testing for familial variants (also called site-specific or known variants testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about testing option, call 800-533-1710.

Specimen preferred to arrive within 96 hours of collection.

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Submit only 1 of the following specimens:

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)4 days/Refrigerated

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

Specimen Type: Cultured fibroblasts

Container/Tube: T-25 flask

Specimen Volume: 2 Flasks

Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.

Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing, Tissue. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

• Informed Consent for Genetic Testing
• Informed Consent for Genetic Testing (Spanish)
• Targeted Genes and Methodology Details for Hyper-IgE Syndrome Gene Panel
• Inborn Errors of Immunity, Autoimmunity, and Autoinflammatory Disease Patient Information

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521)

3. Inborn Errors of Immunity, Autoimmunity, and Autoinflammatory Disease Patient Information

Blood: 1 mL; Skin biopsy or cultured fibroblasts: See Specimen Required

Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of hyper-IgE syndrome (HIES)

Establishing a diagnosis of HIES, allowing for appropriate management and surveillance for disease features based on the gene and/or variant involved

Identifying variants within genes known to be associated with HIES, allowing for predictive testing of at-risk family members and/or determination of targeted management (anticipatory guidance, management changes, specific therapies)

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 21 genes associated with hyper-IgE syndrome: AIRE, CARD11, CARD9, CARMIL2, DOCK8, ERBIN, IL6R, IL6ST, IL17RA, IL17RC, IL17F, PGM3, SPINK5, STAT1, STAT3, TGFBR1, TGFBR2, TRAF3IP2, TYK2, WAS, and ZNF341. See Targeted Genes and Methodology Details for Hyper-IgE Syndrome Gene Panel and Method Description for additional details.

Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for hyper-IgE syndrome.

For skin biopsy or cultured fibroblast specimens, fibroblast culture will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

Hyper IgE syndrome (HIES) is characterized by an increased susceptibility to infection (particularly recurrent skin and pulmonary infections), eczema, and elevated serum IgE. There is variable expression among individuals and additional features may be present, including vascular, skeletal, and connective tissue pathology. While the incidence of HIES is estimated to be between 1:100,000 to 1,000,000 at birth, this may be an underestimate due to incomplete penetrance.

Dominant negative variants in STAT3 were first identified as the genetic cause of HIES, which was referred to as Job syndrome. Now additional genes have been identified, and cases due to STAT3 variants are referred to as STAT3-HIES. Infection in STAT3-HIES is often due to Staphylococcus aureus and Candida species. While HIES may be inherited in an autosomal dominant pattern, many cases are de novo.

Genetic variants in additional genes have been identified that result in HIES. ZNF341 (zinc finger protein 341) deficiency results in an autosomal recessive form of HIES, also known as AR-HIES. Partial deficiency of interleukin (IL) 6 signal transducer (IL6ST) has been reported in both autosomal recessive and autosomal dominant forms of HIES, while complete IL6ST deficiency is typically fatal in utero or early in the neonatal period. Additionally, variants in PGM3, CARD11, and other genes have been identified as causes of HIES. Furthermore, other distinct immunodeficiency disorders or other conditions may have overlapping features with HIES (eg, elevated IgE or severe infection), making the diagnosis challenging. While the phenotypes of disorders leading to elevated IgE and predisposition to infection are often similar, the therapeutic options and treatment strategies differ.

An interpretive report will be provided

All detected variants are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Correlations:
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact Mayo Clinic Laboratories genetic counselors at 800-533-1710.

Technical Limitations:
Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.

There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.

This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.

Deletion/Duplication Analysis:

This analysis targets single and multi-exon deletions/duplications; however, in some instances, single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

Genes may be added or removed based on updated clinical relevance. Refer to the Targeted Genes and Methodology Details for Hyper-IgE Syndrome Gene Panel for the most up to date list of genes included in this test. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.

1. Richards S, Aziz N, Bale S, et al; ACMG Laboratory Quality Assurance Committee: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

2. Tsilifis C, Freeman AF, Gennery AR: STAT3 Hyper-IgE syndrome-an update and unanswered questions. J Clin Immunol. 2021 Jul;41(5):864-880

3. Asano T, Khourieh J, Zhang P, et al: Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance. J Exp Med. 2021 Aug 2;218(8):e20202592. doi: 10.1084/jem.20202592

4. Hsu AP, Davis J, Puck JM, Holland SM, Freeman AF: STAT3 hyper IgE syndrome. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews.[Internet] University of Washington, Seattle; 2010. Updated March 26, 2020. Accessed January 23, 2023. Available at www.ncbi.nlm.nih.gov/books/NBK25507/

5. Tangye SG, Al-Herz W, Bousfiha A, et al: Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022 Oct;42(7):1473-1507. doi: 10.1007/s10875-022-01289-3

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the genes analyzed, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions/insertions (delins) less than 40 base pairs (bp), and above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the genes analyzed.

Varies

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• Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
• Prospective clients should contact their account representative. For assistance, contact Customer Service.

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

81443

88233- Tissue culture, skin, solid tissue biopsy (if appropriate)

88240- Cryopreservation (if appropriate)